%0 Journal Article
%T An integrated transcriptome analysis in T©\cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
%A Jukka Kanerva
%A Kjeld Schmiegelow
%A Linda K£¿hn
%A Magnus Hultdin
%A Mats Heyman
%A Mattias Landfors
%A P£¿r Larsson
%A Sofie Degerman
%A Trond Fl£¿gstad
%A Zahra Haider
%J Archive of "Cancer Medicine".
%D 2019
%R 10.1002/cam4.1917
%X Classification of pediatric T©\cell acute lymphoblastic leukemia (T©\ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T©\ALL patients were characterized by genome©\wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2©\1, and novel genes in T©\ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP£¿ subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL©\TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP£¿), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T©\ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies
%K BEX1
%K DNA methylation
%K HOXA
%K pediatric acute lymphoblastic leukemia
%K TAL1
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346238/